Identification and application of antibiotic synergy

Abstract

The present invention provides a pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective combination of a β-lactam antibiotic and an inhibitor of any bacterial peptidoglycan biosynthesis enzyme, especially GlmU, GlmU, MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY, and UppS. Further provided is a method of discovering synergists for antibiotics including: a) expressing in a cell an antisense nucleic acid against a nucleic acid encoding a gene product so as to reduce the activity or amount of the gene product in the cell, thereby producing a cell sensitized to an antibiotic; b) characterizing the sensitization of the cell to the antibiotic and selecting pairs of antibiotics and genes that result in antibiotic efficacy at one-fifth or less the concentration required in the absence of the antisense gene; c) screening for chemical compounds that inhibit the gene product corresponding to the selected synergistic gene; and d) selecting or creating chemical analogs that inhibit the gene product corresponding to the selected synergistic gene such that the inhibition occurs in the bacteria.

Description

RELATED APPLICATIONS [0001] This application claims priority under §35 U.S.C. 119(e) from provisional application Ser. Nos. 60 / 751,245 filed Dec. 16, 2005 and 60 / 749,299 filed Dec. 9, 2005 which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates generally to bacterial diseases and more specifically to combinations of compounds that enable therapeutic control of bacterial infections at doses of the compounds much lower than either of the compounds administered alone, especially inhibitors of MurB in combination with β-lactam antibiotics. [0004] 2. Background Information [0005] The few available distinct classes of antimicrobial compounds limit the scope for single and combination drug treatment of bacterial infections, including infections involving antibiotic-resistant bacteria. Antibacterial chemotherapy research has therefore focused on the discovery of novel targets for new antibacteria...

AI Technical Summary

Benefits of technology

[0024] In one embodiment, the present invention provides a method of increasing the antibacterial potency of beta-lactam antibiotics, thus having utility in methods for preventing or treating bacterial infections in animals.

[0026] An improved method for identifying microbial gene fragments that, when ectopically expressed in the antisense orientation, results in post-transcriptional inhibition of expression of a microbial gene of interest, thereby causing a phenotypic change in the microorganism that can be observed and measured. Once successfully identified, conditional expression of such antisense-oriented fragments can be used to lower the concentration of the specific gene product within the cell, thereby hypersensitizing the cell to second agents that are themselves specific inhibitors of the gene product. If the observed phenotype constitutes a loss of the ability to proliferate, then this hypersensitivity can be the basis of an assay to test the mechanism of action compounds with antimicrobial activity. Such an assay would be able to distinguish between antimicrobial compounds whose ability to cause loss of proliferation is linked to specific effects on a target gene product of interest, and those compound, and those for which there is no observed link. The improved method would speed development of such assays by definitively identifying the most suitable antisense DNA fragments.

[0030] Focus on a gene or gene of interest rather than the entire genome of an organism. This allows a much greater representation of the gene or gene of interest in the screen for fragments that cause a target-specific phenotypic effect. Using whole genomic DNA to find antisense fragments to a specific gene or genes of interest results in longer screens

Problems solved by technology

The few available distinct classes of antimicrobial compounds limit the scope for single and combination drug treatment of bacterial infections, including infections involving antibiotic-resistant bacteria.

There may be other processes important in limiting the effectiveness of any particular antibiotic.

However, in the case of the β-lactamases, the interaction with the penicillin or cephalosporin results in the hydrolysis of the antibiotic, ruining their ability to interact with PBPs.

None of these studies anticipate that a chemical inhibitor of peptidoglycan biosynthesis enzymes would increase the sensitivity of non-resistant bacteria to beta-lactam antibiotics.

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